This invention is directed to processes for the solid-phase synthesis of aldehyde, ketone, oxime, amine, and hydroxamic acid and xcex1,xcex2-unsaturated carboxylic acid and aldehyde compounds and to polymeric hydroxylamine resin compounds useful therefor.
Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools for preparing amides, peptides and hydroxamic acids. For solid phase peptide synthesis, a summary of the many techniques may be found in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984); J. Meienhofer, Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (New York), 1973; and E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press at Oxford University Press (Oxford, 1989). For the use of solid phase methodology in the preparation of non-peptide molecules see Leznoff, C. C., Acc. Chem. Res., 11, 327-333 (1978).
A number of polymeric reagents have found synthetic use in simple functional group transformations. See A. Akelah and D. C. Sherrington, Application of Functionalized Polymers in Organic Synthesis, Chem Rev., 81, 557-587 (1981) and W. T. Ford and E. C. Blossey, Polymer Supported Reagents, Polymer supported Catalysts, and Polymer Supported Coupling Reactions, in Preparative Chemistry using Supported Reagents, Pierre Laszlo, ed., Academic Press, Inc., 193-212 (1987). For the use of polymeric reagents in oxidation reactions see J. M. J. Frechet et al., J. Org. Chem. 43, 2618 (1978) and G. Cainelli et al., J. Am. Chem. Soc., 98, 6737 (1976). For the use of polymeric reagents in halogenation reactions see J. M. J. Frechet et al., J. Macromol. Sci. Chem., A-11, 507 (1977) and D. C. Sherrington et al., Eur. Polym. J., 13, 73, (1977). For the use of polymeric reagents in epoxidation reactions see J. M. J. Frechet et al., Macromolecules, 8, 130 (1975) and C. R. Harrison et al., J. Chem. Soc. Chem. Commun., 1009 (1974). For the use of polymeric reagents in acylation reactions see M. B. Shambhu et al., Tet. Lett., 1627 (1973) and M. B. Shambhu et al., J. Chem. Soc. Chem. Commun., 619 (1974). For the use of polymeric reagents in Wittig reactions see S. V. McKinley et al., J. Chem. Soc. Chem. Commun., 134 (1972).
Polymeric reagents also have found widespread use in combinatorial synthesis and for preparing combinatorial libraries. See F. Balkenhohl et al., Angew. Chem. Int. Ed. Engl., 35, 2288-2337 (1996) and L. A. Thompson et al., Chem Rev., 96 555-600 (1996).
A polymeric reagent has the advantage of ease of separation from low molecular weight reactants or products by filtration or selective precipitation. The polymeric reagent also can be used in excess to effect fast and quantitative reactions, such as in the case of acylations, or a large excess of reactants may be used to drive the equilibrium of the reaction towards product formation to provide essentially quantitative conversion to product, as in solid phase peptide synthesis. A further advantage of supported reagents and catalysts is the fact that they are recyclable and that they lend easily to automated processes. In addition, supported analogs of toxic and odorous reagents are safer to use.
PCT application publication no. WO96/26223 discloses the synthesis of hydroxamic acid compounds using a solid phase hydroxylamine substrate.
Prasad et al. disclose a O-methylhydroxylamine-polystyrene resin compound in J. Steroid Biochem., 18, 257-261 (1983).
Resin-bound Weinreb-like amides are disclosed by Fehrentz et al., Tet. Lett., 1995, 36, 7871-7874 and Dinh et al., Tet. Lett., 1996, 37, 1161-1164.
Polymeric Horner-Wadsworth-Emmons reagents are disclosed by Wipf et al., J. Org. Chem., 1997, 62, 1586 and Johnson et al., Tetrahedron Lett., 1995, 36, 9253.
This invention is directed to a process for the preparation of a ketone compound of formula 
wherein Rc and Ra are independently aliphatic or aromatic, this process comprising
(a) reacting an N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
is a solid support, L is absent or a linking group and Rb is aliphatic or aryl
with an organometallic reagent of formula RcM wherein Rc is an aliphatic or aryl anion and M is a metal cation; and
(b) liberating the ketone compound from the resin.
In another aspect, this invention is directed to a process for the preparation of an aldehyde compound of formula RaCHO wherein Ra is defined above, comprising
(a) reacting an N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
L and Ra and Rb are defined above;
with a reducing agent; and
(b) liberating the aldehyde compound from the resin.
In another aspect, this invention is directed to a process for the preparation of an N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
L and Ra and Rb are defined above, comprising
(a) coupling a carboxylic acid compound of formula RaCO2H with a polymeric hydroxylamine resin compound of formula 
to form a polymeric hydroxamic acid resin compound of formula 
(b) reacting the polymeric hydroxamic acid resin compound with an alkylating agent of formula RbLG wherein LG is a leaving group.
In another aspect, this invention is directed to a process for the preparation of an N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
L and Ra and Rb are defined above, comprising
(a) reacting an N-protected polymeric hydroxamic acid resin compound of formula 
wherein P is an amine protecting group, with an alkylating agent of formula RbLG wherein LG is defined above, to form a polymeric N-protected N-alkylated hydroxylamine resin compound of formula 
(b) removing the amine protecting group to form a polymeric N-alkylated hydroxylamine resin compound of formula 
(c) coupling the polymeric N-alkylated hydroxylamine resin compound with a carboxylic acid compound of formula RaCO2H.
In another aspect, this invention is directed to a process for preparing a hydroxamic acid compound of formula 
wherein
A2 is a direct bond, alkylene, or NR13;
R13 is hydrogen or alkyl;
R9 is -L1-R14 or -L2-R15;
L1 is a direct bond or alkylene;
R14 is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, cyclocarbamoyl, cycloimidylalkyl, heterocyclyl, heteroaryl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2, (N-carbamoyl)cyclic amine, xe2x80x94Cxe2x95x90Nxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2, xe2x80x94NY1SO2aryl, xe2x80x94NHR13, xe2x80x94SR13 or xe2x80x94OR13;
L2 is alkenylene or alkynylene;
R15 is hydrogen, aryl, carboxy, cyano, cycloalkyl, cycloalkenyl, heterocyclylalkyl or heteroaryl;
R10 and R12 are independently hydrogen or alkyl; or R10 and R12 together form a bond, or R10 and R9 taken together with the carbon atom through which R10 and R9 are attached form spirocycloalkyl;
R11 is a group -L3-R16, or R11 and R9 taken together with the carbon atoms through which R11 and R9 are attached form cycloalkylene; or R11 and R12 taken together with the carbon atom through which R11 and R12 are attached form spirocycloalkyl;
L3 is a direct bond, alkylene, alkenylene or alkynylene;
R16 is hydrogen, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94Cxe2x95x90Nxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94C(xe2x95x90O)xe2x80x94NY1Y2; xe2x80x94NY1SO2aryl, xe2x80x94NR13, xe2x80x94SR13, or xe2x80x94OR13;
Y1 and Y2 are independently selected from hydrogen, alkyl, aralkyl, and aryl, or Y1 and Y2 taken together with the nitrogen atom to which Y1 and Y2 are attached form azaheterocyclyl;
Ar is selected from the group of formulae 
R17 is alkyl, or, when Z3 is a direct bond, then R17 is selected from hydrogen, alkyl, alkenyl and alkynyl;
R18 is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl;
R19 is R20, xe2x80x94OR20, xe2x80x94SR20, xe2x80x94SOR20, xe2x80x94SO2R20, xe2x80x94SO2NR20R21, xe2x80x94NR20SO2R21, xe2x80x94NR20R21, xe2x80x94O(Cxe2x95x90O)NR20R21, xe2x80x94NR20C(xe2x95x90O)R21, xe2x80x94N(OH)C(xe2x95x90O)R20, or xe2x80x94C(xe2x95x90O)N(OH)R21,
R20 and R21 are independently hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, aralkyl or heteroaralkyl; or R20 and R21 taken together with the nitrogen atom to which R20 and R21 are attached form azaheterocyclyl;
A3 is a direct bond, alkylene, alkenylene or alkynylene;
Z1 and Z3 are independently a direct bond, oxygen, sulfur or NH;
Z2 is a direct bond, oxygen or sulfur;
B, C, D, and E are independently CH or a heteroatom selected from O, S, N, NOR22 and NR22, or three of B, C, D and E are independently CH or a heteroatom selected from O, S, N or NR22, and the other of B, C, D and E is a direct bond; and one of B, C, D and E that are in adjacent positions is other than O or S;
R22 is hydrogen, alkyl, aryl, lower aralkyl, heteroaryl or lower heteroaralkyl;
Q1, Q2 and Q3 independently are CH, CX1 or N;
X1 is halogen; and
n is 0, 1 or 2; or
a prodrug thereof, acid isostere thereof, pharmaceutically acceptable salt thereof, or solvate thereof,
this process comprising treating a polymeric hydroxamic acid resin compound of formula 
with acid.
In another aspect, this invention is directed to a process for the preparation of a polymeric oxime ether resin compound of formula 
wherein 
and L are as defined herein and Rd and Re are independently H, aliphatic or aromatic, this process comprising reacting a polymeric hydroxylamine resin compound of formula 
with a carbonyl compound of formula 
In another aspect, this invention is directed to a process for the preparation of an xcex1-amine compound of formula 
wherein Rd and Re are independently H, aliphatic or aryl, provided that Rd and Re are not both H, comprising reductively cleaving a polymeric oxime ether resin compound of formula 
wherein 
and L are as defined herein.
In another aspect, this invention is directed to a process for the preparation of a substituted xcex1-amine compound of formula 
wherein Rd and Re are independently H, aliphatic or aromatic, provided that Rd and Re are not both H, and Rf is aliphatic or aromatic, comprising
(a) reacting a polymeric oxime ether compound of formula 
wherein 
and L are as defined herein, with an organometallic reagent of formula RfM wherein Rf is an aliphatic or aromatic anion and M is a metal cation, to form a polymeric xcex1-substituted hydroxylamine resin compound of formula 
(b) reductively cleaving the xcex1-substituted hydroxylamine resin compound.
In another aspect, this invention is directed to a process for the preparation of a lactone compound of formula 
wherein Rg, Rh and Ri are independently aliphatic or aromatic and Ph is phenyl, comprising
(a) treating an xcex1,xcex2-unsaturated polymeric hydroxamic acid ester resin compound of formula 
wherein 
and L are as defined herein, with thiophenol and a free radical initiator to form a polymeric oximyl lactone compound of formula 
(b) treating the polymeric oximyl lactone compound with aqueous acid.
In another aspect, this invention is directed to a process for the preparation of an xcex1,xcex2-unsaturated polymeric hydroxamic acid ester resin compound of formula 
wherein 
L and Rg and Rh and Ri are as defined herein, comprising reacting a polymeric hydroxylamine resin compound of formula 
with an xcex1,xcex2-unsaturated carboxylic acid ester compound of formula 
In another aspect, this invention is directed to a process for the preparation of an xcex1-cyclic hydroxylamine compound of formula 
wherein Rj and Rk are aliphatic or aromatic and Q is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94, comprising
(a) treating a polymeric acetophenone oxime compound of formula 
wherein 
and L are as defined herein, with trialkyltin hydride and a free radical initiator to form a polymeric xcex1-cyclic hydroxylamine resin compound of formula 
(b) treating the polymeric xcex1-cyclic hydroxylamine resin compound with aqueous acid.
In another aspect, this invention is directed to a process for the preparation of an xcex1-cyclic amino compound of formula 
wherein Rj and Rk are aliphatic or aromatic and Q is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94, comprising reductively cleaving a polymeric xcex1-cyclic hydroxylamine resin compound of formula 
wherein 
and L are as defined herein.
In another aspect, this invention is directed to a process for the preparation of an xcex1-cyclic hydroxylamine compound of formula 
wherein Rj, Rk and Rl are aliphatic or aromatic and Q is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94, comprising
(a) treating a polymeric acetophenone oxime compound of formula 
wherein 
and L are as defined herein, with trialkyltin hydride and a free radical initiator to form a polymeric xcex1-cyclic hydroxylamine resin compound of formula 
(b) treating the polymeric xcex1-cyclic hydroxylamine resin compound with aqueous acid.
In another aspect, this invention is directed to a process for the preparation of an xcex1-cyclic amino compound of formula 
wherein Rj, Rk and Rl are aliphatic or aromatic and Q is xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94, comprising reductively cleaving a polymeric xcex1-cyclic hydroxylamine resin compound of formula 
wherein 
and L are as defined herein.
In another aspect, this invention is directed to an N-protected hydroxylamine resin compound of formula 
wherein 
and L are as defined herein and P is an amine protecting group, provided that P is other than 4-methoxybenzyl or 2,4-dimethoxybenzyl.
In another aspect, this invention is directed to a polymeric fluorophenyl hydroxylamine resin compound of formula 
wherein 
A, R3 and R4 are as defined herein, P1 is an amine protecting group, and R28, R29, and R30 are ring system substituents, or R28 and R29 taken together with the carbon atoms through which they are linked form a 6 membered aryl or a 5 to 6 membered heteroaryl.
In another aspect, this invention is directed to a process for preparing an xcex1,xcex2-unsaturated alkenoate resin compound of formula 
wherein 
and L are as defined herein; Rm is H or aliphatic; and Rn is aliphatic or aromatic, comprising
(a) treating a mixture in a reaction vessel of a first solvent and a polymeric phosphonoacetoxy resin compound of formula 
wherein R20 and R20 are alkyl, with excess base;
(b) draining the solvent from the reaction vessel; and
(c) adding a solution of an aldehyde of formula RnCHO in a less polar second solvent.
In another aspect, this invention relates to the N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
is a solid support containing one or more fluorine atoms.
In another aspect, this invention is directed to the use of the N-alkylated polymeric hydroxamic acid resin compound of formula 
wherein 
is a solid support containing one or more fluorine atoms, for the solid-phase synthesis of aldehyde, ketone, oxime, amine, and hydroxamic acid and xcex1,xcex2-unsaturated carboxylic acid and aldehyde compounds, wherein the solid support containing one or more fluorine atoms facilitates monitoring and quantifying the solid-phase reactions by 19F NMR. A detailed discussion of the method of quantifying solid-phase reactions by 19F NMR, and the synthesis of fluorinated resins is described in PCT/US98/26512 filed Dec. 14, 1998, the contents of which are incorporated herein by reference.
Definitions of Terms
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
xe2x80x9cSolid supportxe2x80x9d means a substrate which is inert to the reagents and reaction conditions described herein, as well as being substantially insoluble in the media used. Representative solid supports include inorganic substrates such as kieselguhr, silica gel, and controlled pore glass; organic polymers including polystyrene, including 1-2% copolystyrene divinyl benzene (gel form) and 20-40% copolystyrene divinyl benzene (macroporous form), polypropylene, polyethylene glycol, polyacrylamide, cellulose, and the like; and composite inorganic/polymeric compositions such as polyacrylamide supported within a matrix of kieselguhr particles. See J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pierce Chemical Co. (Chicago, Ill., 1984). Solid support is designated generally as 
throughout the description.
In addition, xe2x80x9csolid supportxe2x80x9d includes a solid support as described above which is affixed to a second inert support such as the pins described in Technical Manual, Multipin(trademark) SPOC, Chiron Technologies (1995) and references therein which comprise a detachable polyethylene- or polypropylene-based head grafted with an amino functionalized methacrylate copolymer and an inert stem.
In addition, xe2x80x9csolid supportxe2x80x9d includes polymeric supports such as the polyethylene glycol supports described by Janda et al., Proc. Natl. Acad. Sci. USA, 92, 6419-6423 (1995) and S. Brenner, WO 95/16918, which are soluble in many solvents but can be precipitated by the addition of a precipitating solvent.
In addition xe2x80x9csolid supportxe2x80x9d includes polymeric supports as described above, containing one or more fluorine atoms. Polymeric supports containing one or more fluorine atoms are prepared by polymerization using methods known in the art so as to incorporate one or more fluorine-containing monomers into the solid support. Representative suitable fluorine-containing monomers include 4-fluorostyrene, 4-trifluoromethylstyrene, 2-fluoro-4-vinylbenzyl chloride and the like. Polymeric supports containing one or more fluorine atoms are readily prepared, for example by copolymerizing mixtures of 4-fluorostyrene, styrene, 1,4-divinylbenzene and 4-vinylbenzyl chloride. A detailed discussion of the method of synthesizing fluorinated resins is described in PCT/US98/26512 filed Dec. 14, 1998, the contents of which are incorporated herein by reference. Solid supports containing one or more fluorine atoms may be designated as 
throughout the description.
xe2x80x9cPolymeric hydroxylamine resin compoundxe2x80x9d means a solid support as defined above which is chemically modified as is known in the art to incorporate a plurality of hydroxylamine (xe2x80x94ONH2) or protected hydroxylamine (xe2x80x94ONHP) groups. The hydroxylamine or protected hydroxylamine groups are covalently bound directly to the solid support or attached to the solid support by covalent bonds through a linking group. The polymeric hydroxylamine resin compounds according to the process aspect of this invention are designated herein as 
wherein 
is a solid support as defined herein, L is absent or a linking group and P is an amine protecting group.
xe2x80x9cLinking groupxe2x80x9d and xe2x80x9clinkerxe2x80x9d mean a group through which the amino, aminomethyl or other functionality may be covalently linked to the solid support. The linking group is generally inert to the reagents and reaction conditions described herein.
xe2x80x9cAmine protecting groupxe2x80x9d means an easily removable group which is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of N-protecting groups is well known in the art for protecting nitrogen-containing groups against undesirable reactions during a synthetic procedure, and many such protecting groups are known. CF, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Preferred N-protecting groups are acyl, including formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like, and acyloxy, including methoxycarbonyl; 9-fluorenylmethoxycarbonyl; 2,2,2-trifluoroethoxycarbonyl; 2-trimethylsilylethxoycarbonyl; vinyloxycarbonyl; allyloxycarbonyl; t-butyloxycarbonyl (BOC); 1,1-dimethylpropynyloxycarbonyl; benzyloxycarbonyl (CBZ); p-nitrophenylsulfinyl; p-nitrobenzyloxycarbonyl;
2,4-dichlorobenzyloxycarbonyl; allyloxycarbonyl (Alloc), and the like.
xe2x80x9cCarboxylic acid protecting groupxe2x80x9d and xe2x80x9cacid protecting groupxe2x80x9d mean an easily removable group which is known in the art to protect a carboxylic acid (xe2x80x94CO2H) group against undesirable reaction during synthetic procedures and to be selectively removable. The use of carboxylic acid protecting groups is well known in the art, and many such protecting groups are known. CF, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), the contents of which are hereby incorporated herein by reference. Examples of carboxylic acid protecting groups include esters such as methoxymethyl, methylthiomethyl, tetrahydropyranyl, benzyloxymethyl, substituted and unsubstituted phenacyl, 2,2,2-trichloroethyl, tert-butyl, cinnamyl, substituted and unsubstituted benzyl, trimethylsilyl, allyl, and the like, and amides and hydrazides including N,N-dimethyl, 7-nitroindolyl, hydrazide, N-phenylhydrazide, and the like. Especially preferred carboxylic acid protecting groups are tert-butyl and benzyl.
xe2x80x9cHydroxy protecting groupxe2x80x9d means an easily removable group which is known in the art to protect a hydroxy group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy protecting groups is well known in the art, and many such protecting groups are known. See., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). Examples of hydroxy protecting groups include ethers such as methyl; substituted methyl ethers such as methoxymethyl (MOM), methylthiomethyl (MTM), 2-methoxyethoxymethyl (MEM), bis(2-chloroethoxy)methyl, tetrahydropyranyl (THP), tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, and the like; substituted ethyl ethers such as 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, benzyl, o-nitrobenzyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, 9-(9-phenyl-10-oxo)anthranyl (tritylone), and the like; silyl ethers such as trimethylsilyl (TMS), isopropyldimethylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triisopropylsilyl, and the like; esters such as formate, acetate, trichloroacetate, phenoxyacetate, isobutyrate, pivaloate, adamantoate, benzoate, 2,4,6-trimethylbenzoate, and the like; and carbonates such as methyl, 2,2,2-trichloroethyl, allyl, p-nitrophenyl, benzyl, p-nitrobenzyl, S-benzyl thiocarbonate, and the like.
xe2x80x9cAmino acidxe2x80x9d means an amino acid selected from the group consisting of natural and unnatural amino acids as defined herein.
xe2x80x9cNatural amino acidxe2x80x9d means an xcex1-amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid and glutamic acid.
xe2x80x9cUnnatural amino acidxe2x80x9d means an amino acid for which there is no nucleic acid codon. Examples of unnatural amino acids include, for example, the D-isomers of the natural xcex1-amino acids as indicated above; aminobutyric acid (Aib), 3-aminoisobutyric acid (bAib), norvaline (Nva), xcex2-Ala, 2-aminoadipic acid (Aad), 3-aminoadipic acid (bAad), 2-aminobutyric acid (Abu), xcex3-aminobutyric acid (Gaba), 6-aminocaproic acid (Acp), 2,4-diaminobutryic acid (Dbu), xcex1-aminopimelic acid, trimethylsilyl-Ala (TMSA), allo-isoleucine (alle), norleucine (Nle), tert-Leu, citrulline (Cit), ornithine (Orn), 2,2xe2x80x2-diaminopimelic acid) (Dpm), 2,3-diaminopropionic acid (Dpr), xcex1- or xcex2-Nal, cyclohexyl-Ala (Cha), hydroxyproline, sarcosine (Sar), and the like; cyclic amino acids; Nxcex1-alkylated amino acids such as Nxcex1-methylglycine (MeGly), Nxcex1-ethylglycine (EtGly) and Nxcex1-ethylasparagine (EtAsn); and amino acids in which the xcex1-carbon bears two side-chain substituents.
xe2x80x9cEquivalent amino acidxe2x80x9d means an amino acid which may be substituted for another amino acid in the peptides according to the invention without any appreciable loss of function. In making such changes, substitutions of like amino acids is made on the basis of relative similarity of side chain substituents, for example regarding size, charge, hydrophilicity, hydropathicity and hydrophobicity as described herein.
xe2x80x9cPeptidexe2x80x9d and xe2x80x9cpolypeptidexe2x80x9d mean a polymer in which the monomers are natural or unnatural amino acid residues joined together through amide bonds. The term xe2x80x9cpeptide backbonexe2x80x9d means the series of amide bonds through which the amino acid residues are joined. The term xe2x80x9camino acid residuexe2x80x9d means the individual amino acid units incorporated into the peptides or polypeptides.
xe2x80x9cAliphaticxe2x80x9d means a radical derived from a non aromatic Cxe2x80x94H bond by removal of the hydrogen atom. The aliphatic radical may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aliphatic groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aralkenyl, aralkyloxyalkyl, aralkyloxycarbonylalkyl, aralkyl, aralkynyl, aralkyloxyalkenyl, heteroaralkenyl, heteroaralkyl, heteroaralkyloxyalkenyl, heteroaralkyloxyalkyl, heteroaralkynyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, and the like. xe2x80x9cAliphaticxe2x80x9d, as used herein, also encompasses the residual, non-carboxyl portion of natural and unnatural amino acids as defined herein.
xe2x80x9cAromaticxe2x80x9d means a radical derived from an aromatic Cxe2x80x94H bond by removal of the hydrogen atom. Aromatic includes both aryl and heteroaryl rings as defined herein. The aryl or heteroaryl ring may be further substituted by additional aliphatic or aromatic radicals as defined herein. Representative aromatic groups include aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, fused heterocyclylheteroaryl, and the like.
xe2x80x9cAcid bioisosterexe2x80x9d means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxylic group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 xe2x80x9cBioisosterism In Drug Designxe2x80x9d; Yun, Hwahak Sekye, 1993,33,p576-579 xe2x80x9cApplication Of Bioisosterism To New Drug Designxe2x80x9d; Zhao, Huaxue Tongbao, 1995,p34-38 xe2x80x9cBioisosteric Replacement And Development Of Lead Compounds In Drug Designxe2x80x9d; Graham, Theochem, 1995,343,p105-109 xe2x80x9cTheoretical Studies Applied To Drug Design: ab initio Electronic Distributions In Bioisosteresxe2x80x9d). Examples of suitable acid bioisosteres include: xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2OH, xe2x80x94C(xe2x95x90O)xe2x80x94CH2SH, xe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94CN, sulpho, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group wherein the alkyl group is as herein described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAlkenoylxe2x80x9d means an alkenyl-COxe2x80x94 group wherein alkenyl is as defined herein.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbonxe2x80x94carbon double bond. Preferred alkenyl groups have 2 to about 12 carbon atoms; more preferred alkenyl groups have 2 to about 4 carbon atoms. The alkenyl group is optionally substituted with one or more alkyl group substituents as defined herein. Representative alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
xe2x80x9cAlkenyloxyxe2x80x9d means an alkenyl-Oxe2x80x94 group wherein the alkenyl group is as herein described. Representative alkenyloxy groups include allyloxy or 3-butenyloxy.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group wherein the alkyl group is as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl-O-alkylene- group wherein alkyl and alkylene are as defined herein. Representative alkoxyalkyl groups include methoxyethyl, ethoxymethyl, n-butoxymethyl and cyclopentylmethyloxyethyl.
xe2x80x9cAlkoxyalkoxyxe2x80x9d means an alkyl-O-alkylenyl-Oxe2x80x94 group. Representative alkoxyalkoxy include methoxymethoxy, methoxyethoxy, ethoxyethoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an ester group; i.e. an alkyl-Oxe2x80x94COxe2x80x94 group wherein alkyl is as defined herein. Representative alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d means an alkyl-O-CO-alkylenexe2x80x94 group wherein alkyl and alkylene are as defined herein. Representative alkoxycarbonylalkyl include methoxycarbonylmethyl, and ethoxycarbonylmethyl, methoxycarbonyl ethyl, and the like.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group, which may be straight or branched-chain, having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means 1 to about 4 carbon atoms in the chain, which may be straight or branched. The alkyl is optionally substituted with one or more xe2x80x9calkyl group substituentsxe2x80x9d which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, carbamoyl, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, or heteroaralkyloxycarbonyl. Representative alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, and pyridylmethyloxycarbonylmethyl.
xe2x80x9cAlkylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain of 1 to about 6 carbon atoms. The alkylene is optionally substituted with one or more xe2x80x9calkylene group substituentsxe2x80x9d which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, carbamoyl, carboxy, cyano, aryl, heteroaryl or oxo. The alkylene is optionally interrupted by, i.e., a carbon thereof is substituted by, xe2x80x94Oxe2x80x94, xe2x80x94S(O)m (where m is 0-2), phenylene or xe2x80x94NRxe2x80x2xe2x80x94 (where Rxe2x80x2 is lower alkyl). Preferred alkylene groups are the lower alkylene groups having 1 to about 4 carbon atoms. Representative alkylene groups include methylene, ethylene, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain containing at least one carbonxe2x80x94carbon double bond. The alkenylene is optionally substituted with one or more xe2x80x9calkylene group substituentsxe2x80x9d as defined herein. The alkenylene is optionally interrupted by, i.e., a carbon thereof is substituted by, xe2x80x94Oxe2x80x94, xe2x80x94S(O)m (where m is 0-2), phenylene or xe2x80x94NRxe2x80x2xe2x80x94 (where Rxe2x80x2 is lower alkyl). Representative alkenylene include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like.
xe2x80x9cAlkynylenexe2x80x9d means a straight or branched bivalent hydrocarbon chain containing at least one carbonxe2x80x94carbon triple bond. The alkynylene is optionally substituted with one or more xe2x80x9calkylene group substituentsxe2x80x9d as defined herein. The alkynylene is optionally interrupted by, i.e., a carbon thereof is substituted for, xe2x80x94Oxe2x80x94, xe2x80x94S(O)m (where m is 0-2), phenylene or xe2x80x94NRxe2x80x2xe2x80x94 (where Rxe2x80x2 is lower alkyl). Representative alkynylene include 
and the like.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group wherein the alkyl group is as defined above. Preferred alkylsulfinyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2-group wherein the alkyl group is as defined herein. Preferred alkylsulfonyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfonylcarbamoylxe2x80x9d means an alkyl-SO2xe2x80x94NHxe2x80x94COxe2x80x94 group wherein alkyl group is defined herein. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is lower alkyl.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group wherein the alkyl group is as defined herein. Preferred alkylthio groups are those wherein the alkyl group is lower alkyl. Representative alkylthio groups include methylthio, ethylthio, i-propylthio, heptylthio, and the like.
xe2x80x9cAlkynylxe2x80x9d means a straight or branched aliphatic hydrocarbon group of 2 to about 15 carbon atoms which contains at least one carbonxe2x80x94carbon triple bond. Preferred alkynyl groups have 2 to about 12 carbon atoms. More preferred alkynyl groups contain 2 to about 4 carbon atoms. xe2x80x9cLower alkynylxe2x80x9d means alkynyl of 2 to about 4 carbon atoms. The alkynyl group may be substituted by one or more alkyl group substituents as defined herein. Representative alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl, decynyl, and the like.
xe2x80x9cAlkynyloxyxe2x80x9d means an alkynyl-Oxe2x80x94 group wherein the alkynyl group is as defined herein. Representative alkynyloxy groups include propynyloxy, 3-butynyloxy, and the like.
xe2x80x9cAlkynyloxyalkylxe2x80x9d means alkynyl-O-alkylenexe2x80x94 group wherein alkynyl and alkylene are as defined herein.
xe2x80x9cAmidinoxe2x80x9d or xe2x80x9camidinexe2x80x9d means a group of formula 
wherein R25 is hydrogen; R27O2Cxe2x80x94 wherein R27 is hydrogen, alkyl, aralkyl or heteroaralkyl; R27Oxe2x80x94; R27C(O)xe2x80x94; cyano; alkyl; nitro; or amino, and R26 is selected from hydrogen; alkyl; aralkyl; and heteroaralkyl.
xe2x80x9cAminoxe2x80x9d means a group of formula Y1Y2Nxe2x80x94 wherein Y and Y are independently hydrogen; acyl; or alkyl, or Y1 and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered azaheterocyclyl. Representative amino groups include amino (H2Nxe2x80x94), methylamino, dimethylanino, diethylamino, and the like.
xe2x80x9cAminoalkylxe2x80x9d means an amino-alkylene-group wherein amino and alkylene are defined herein. Representative aminoalkyl groups include aminomethyl, aminoethyl, dimethylaminomethyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means an aryl-alkenylene-group wherein aryl and alkenylene are as defined herein. Preferred aralkenyls contain a lower alkenylene moiety. A representative aralkenyl group is 2-phenethenyl.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group wherein aralkyl is defined herein. Representative aralkyloxy groups include benzyloxy, naphth-1-ylmethoxy, naphth-2-ylmethoxy, and the like.
xe2x80x9cAralkyloxyalkylxe2x80x9d means an aralkyl-O-alkylene- group wherein aralkyl and alkylene are as defined herein. A representative aralkyloxyalkyl group is benzyloxyethyl.
xe2x80x9cAralkyloxycarbonylxe2x80x9d means an aralkyl-Oxe2x80x94COxe2x80x94 group wherein aralkyl is as defined herein. A representative aralkoxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cAralkyloxycarbonylalkylxe2x80x9d means an aralkoxycarbonyl-alkylene-group wherein aralkyloxycarbonyl and alkylene are as defined herein. Representative aralkoxycarbonylalkyls include benzyloxycarbonylmethyl, and benzyloxycarbonylethyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkylene-group wherein aryl and alkylene are as defined herein. Preferred aralkyls contain a lower alkyl moiety. Representative aralkyl groups include benzyl, 2-phenethyl, naphthlenemethyl, and the like.
xe2x80x9cAralkyloxyalkenylxe2x80x9d means an aralkyl-O-alkenylene-group wherein aralkyl and alkenylene are as defined herein. A representative aralkyloxyalkenyl group is 3-benzyloxyallyl.
xe2x80x9cAralkylsulfonylxe2x80x9d means an aralkyl-SO2xe2x80x94 group wherein aralkyl is as defined herein.
xe2x80x9cAralkylsulfinylxe2x80x9d means an aralkyl-SOxe2x80x94 group wherein aralkyl is as defined herein.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group wherein aralkyl is as defined herein. A representative aralkylthio group is benzylthio.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group wherein aryl is defined herein. Representative aroyl include benzoyl, naphth-1-oyl and naphth-2-oyl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 6 ring atoms. The cycloalkyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein, or where R18 is a substituted cycloalkyl, the cycloalkyl is substituted by one or more (e.g. 1, 2 or 3) substituents chosen from OR23, SR24, SOR24, SO2R24, NH2, NR22R24, xe2x95x90NOR24, xe2x95x90NOH, xe2x95x90NNHR24, xe2x95x90NOCONHR24, xe2x95x90NCO2R24, SOR24, NHCOR24, NHSO2R24, SO2NR22R24, R23, CONHR24, CONHCH2CO2R22, CONR24R22, N3 or azaheterocyclyl; wherein R22 is as defined herein; R23 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and R24 is alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl. Representative monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and the like. Representative multicyclic cycloalkyl include 1-decalin, norbornyl, adamantyl, and the like. The prefix spiro before cycloalkyl means that geminal substituents on a carbon atom are replaced to form 1,1-cycloalkyl. xe2x80x9cCycloalkylenexe2x80x9d means a bivalent cycloalkyl having about 4 to about 8 carbon atoms. Preferred cycloalkylenyl groups include 1,2-, 1,3-, or 1,4-cis or trans-cyclohexylene.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, preferably of about 5 to about 10 carbon atoms which contains at least one carbonxe2x80x94carbon double bond. Preferred cycloalkylene rings contain about 5 to about 6 ring atoms. The cycloalkenyl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. A representative multicyclic cycloalkenyl is norbornylenyl.
xe2x80x9cCyclocarbamoylalkylxe2x80x9d means a compound of formula 
in which the cyclocarbamoyl group consists of the oxooxazaheterocyclyl ring moiety, and the alkylene group is as defined herein. The alkylene moiety may be attached to the carbamoyl through either a carbon atom or the nitrogen atom of the carbamoyl moiety. An exemplary cyclocarbamoylalkyl group is N-oxazolidinylpropyl.
xe2x80x9cCycloimidylalkylxe2x80x9d means a compound of formula 
in which the imide group consists of the oxodiazaheterocyclyl ring moiety, and alkylene is as defined herein. The alkylene moiety may be attached to the carbamoyl through either a carbon atom or nitrogen atom of the carbamoyl moiety. An exemplary cycloimidylalkyl group is N-phthalimidepropyl.
xe2x80x9cHeterocyclenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbonxe2x80x94carbon double bond or carbon-nitrogen double bond. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The heterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Representative oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. A representative multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Representative monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like
xe2x80x9cHeterocyclylxe2x80x9d means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein, or wherein R18 is a substituted heterocyclyl, the heterocyclyl is substituted the ring carbon atoms by one or more (e.g. 1, 2 or 3) substituents chosen from oxo, cyano, CO2R22, CONHCH2CO2R22, aryl, arylalkyl, alkyl or hydroxyalkyl, or is substituted on a ring nitrogen atom by a substituent chosen from R22, (CH2)nCO2H, (CH2)nCO2R24, (CH2)nCONR22R24, (CH2)nCOR24, CONH2, CONHR24, COR24, SO2R24, or OR24, wherein R22 and R24 are as defined herein. The nitrogen or sulphur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
xe2x80x9cArylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. The aryl is optionally substituted with one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. Representative aryl groups include phenyl and naphthyl.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. The xe2x80x9cheteroarylxe2x80x9d is optionally substituted by one or more xe2x80x9cring system substituentsxe2x80x9d which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.
xe2x80x9cFused arylcycloalkenylxe2x80x9d means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the cycloalkenyl portion. Preferred fused arylcycloalkenyls are those wherein aryl is phenyl and the cycloalkenyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkenyl include 1,2-dihydronaphthalene, indene, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylarylxe2x80x9d means a radical derived from a fused aryl and cycloalkenyl as defined herein by removal of hydrogen atom from the aryl portion. Representative fused cycloalkenylaryl are as described herein for a fused arylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylcycloalkylxe2x80x9d means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of about 5 to about 6 ring atoms. The fused arylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. Representative fused arylcycloalkyl includes 1,2,3,4-tetrahydronaphthyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylarylxe2x80x9d means a radical derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused cycloalkylaryl are as described herein for a fused arylcycloalkyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclenylxe2x80x9d means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused arylheterocyclenyls are those wherein aryl is phenyl and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl portion of the fused arylheterocyclenyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused arylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused arylheterocyclenyl include 3H-indolinyl, 1H-2-oxoquinolyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydroisoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclenylarylxe2x80x9d means a radical derived from a fused aryl and heterocyclenyl as defined herein by removal of a hydrogen atom from the aryl portion. Representative fused heterocyclenylaryl are as defined herein for a fused arylheterocyclenyl radical, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused arylheterocyclylxe2x80x9d means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused arylheterocyclyls are those wherein aryl is phenyl and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused arylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen or sulphur atom of the heterocyclyl portion of the fused arylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative preferred fused arylheterocyclyl ring systems include phthalimide, 1,4-benzodioxane, indolinyl, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenz[f]isoindolyl, 1,2,3,4-tetrahydrobenz[g]isoquinolinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylarylxe2x80x9d means a radical derived from a fused aryl and heterocyclyl as defined herein by removal of a hydrogen atom from the heterocyclyl portion. Representative preferred fused heterocyclylaryl ring systems are as described for fused arylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylcycloalkenylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the cycloalkenyl portion. Preferred fused heteroarylcycloalkenyls are those wherein the heteroaryl and the cycloalkenyl each contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylcycloalkenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkenyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkenyl include 5,6-dihydroquinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydrobenzoxazolyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkenylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkenyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkenylheteroaryl are as described herein for fused heteroarylcycloalkenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylcycloalkylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred fused heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the cycloalkyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylcycloalkyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylcycloalkyl is optionally oxidized to the corresponding N-oxide. Representative fused heteroarylcycloalkyl include 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydrobenzoxazolyl, 1H4-oxa-1,5-diazanaphthalen-2-onyl, 1,3-dihydroimidizole-[4,5]-pyridin-2-onyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused cycloalkylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Representative fused cycloalkylheteroaryl are as described herein for fused heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclenylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heterocyclenyl portion. Preferred fused heteroarylheterocyclenyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclenyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before heteroaryl or heterocyclenyl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The fused heteroarylheterocyclenyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclenyl portion of the fused heteroarylheterocyclenyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclenyl include 7,8-dihydro[1,7]naphthyridinyl, 1,2-dihydro[2,7]naphthyridinyl, 6,7-dihydro-3H-imidazo[4,5-c]pyridyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl, 1,2-dihydro-2,6-naphthyridinyl, and the like, in which the bond to the parent moiety is through a non aromatic carbon atom.
xe2x80x9cFused heterocyclenylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclenyl as defined herein by the removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclenylheteroaryl are as described herein for fused heteroarylheterocyclenyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cFused heteroarylheterocyclylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heterocyclyl portion. Preferred fused heteroarylheterocyclyls are those wherein the heteroaryl thereof consists of about 5 to about 6 ring atoms and the heterocyclyl consists of about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl or heterocyclyl portion of the fused heteroarylheterocyclyl means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The fused heteroarylheterocyclyl is optionally substituted by one or more ring system substituents, wherein xe2x80x9cring system substituentxe2x80x9d is as defined herein. The nitrogen atom of the heteroaryl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide. The nitrogen or sulphur atom of the heterocyclyl portion of the fused heteroarylheterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Representative fused heteroarylheterocyclyl include 2,3-dihydro-1H pyrrol[3,4-b]quinolin-2-yl, 1,2,3,4-tetrahydrobenz [b][1,7]naphthyridin-2-yl, 1,2,3,4-tetrahydrobenz [b][1,6]naphthyridin-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2-yl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indol-2-yl, 2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl, 1H-2,3,4,5-tetrahydroazepino[4,3-b]indol-3-yl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2 yl, 5,6,7,8-tetrahydro[1,7]napthyridinyl, 1,2,3,4-tetrhydro[2,7]naphthyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pryidyl, 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]napthyridinyl, 1,2,3,4-tetrahydro[1,6]napthyridinyl, 1,2,3,4-tetrahydro[1,7]napthyridinyl, 1,2,3,4-tetrahydro[1,8]napthyridinyl, 1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like, in which the bond to the parent moiety is through a non-aromatic carbon atom.
xe2x80x9cFused heterocyclylheteroarylxe2x80x9d means a radical derived from a fused heteroaryl and heterocyclyl as defined herein, by removal of a hydrogen atom from the heteroaryl portion. Representative fused heterocyclylheteroaryl are as described herein for fused heteroarylheterocyclyl, except that the bond to the parent moiety is through an aromatic carbon atom.
xe2x80x9cAralkynylxe2x80x9d means an aryl-alkynylene- group wherein aryl and alkynylene are defined herein. Representative aralkynyl groups include phenylacetylenyl and 3-phenylbut-2-ynyl.
xe2x80x9cAryldiazoxe2x80x9d means an aryl-Nxe2x95x90N- group wherein aryl is defined herein. Representative aryldiazo groups include phenyldiazo and naphthyldiazo.
xe2x80x9cArylcarbamoylxe2x80x9d means an aryl-NHCOxe2x80x94 group, wherein aryl is defined herein.
xe2x80x9cBenzylxe2x80x9d means a phenyl-CH2xe2x80x94 group. Substituted benzyl means a benzyl group in which the phenyl ring is substituted with one or more ring system substituents. Representative benzyl include 4-bromobenzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, and the like.
xe2x80x9cCarbamoylxe2x80x9d means a group of formula Y1Y2NCOxe2x80x94 wherein Y1 and Y2 are defined herein. Representative carbamoyl groups include carbamyl (H2NCOxe2x80x94), dimethylaminocarbamoyl (Me2NCOxe2x80x94), and the like.
xe2x80x9cCarboxyxe2x80x9d and xe2x80x9ccarboxylxe2x80x9d mean a HO(O)Cxe2x80x94 group (i.e. a carboxylic acid).
xe2x80x9cCarboxyalkylxe2x80x9d means a HO(O)C-alkylene- group wherein alkylene is defined herein. Representative carboxyalkyls include carboxymethyl and carboxyethyl.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyl-Oxe2x80x94 group wherein cycloalkyl is as defined herein. Representative cycloalkyloxy groups include cyclopentyloxy, cyclohexyloxy, and the like.
xe2x80x9cDiazoxe2x80x9d means a bivalent xe2x80x94Nxe2x95x90Nxe2x80x94 radical.
xe2x80x9cEthylenylxe2x80x9d means a xe2x80x94CHxe2x95x90CHxe2x80x94 group.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d mean fluoro, chloro, bromo, or iodo.
xe2x80x9cHeteroaralkenylxe2x80x9d means a heteroaryl-alkenylene- group wherein heteroaryl and alkenylene are as defined herein. Preferred heteroaralkenyls contain a lower alkenylene moiety. Representative heteroaralkenyl groups include 4-pyridylvinyl, thienylethenyl, pyridylethenyl, imidazolylethenyl, pyrazinylethenyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a heteroaryl-alkylene- group wherein heteroaryl and alkylene are as defined herein. Preferred heteroaralkyls contain a lower alkylene group. Representative heteroaralkyl groups include thienylmethyl, pyridylmethyl, imidazolylmethyl, pyrazinylmethyl, and the like.
xe2x80x9cHeteroaralkyloxyxe2x80x9d means an heteroaralkyl-Oxe2x80x94 group wherein heteroaralkyl is as defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxy.
xe2x80x9cHeteroaralkyloxyalkenylxe2x80x9d means a heteroaralkyl-O-alkenylene- group wherein heteroaralkyl and alkenylene are as defined herein. A representative heteroaralkyloxyalkenyl group is 4-pyridylmethyloxyallyl.
xe2x80x9cHeteroaralkyloxyalkylxe2x80x9d means a heteroaralkyl-O-alkylene- group wherein heteroaralkyl and alkylene are as defined herein. A representative heteroaralkyloxy group is 4-pyridylmethyloxyethyl.
xe2x80x9cHeteroaralkynylxe2x80x9d means an heteroaryl-alkynylene- group wherein heteroaryl and alkynylene are as defined herein. Preferred heteroaralkynyls contain a lower alkynylene moiety. Representative heteroaralkynyl groups include pyrid-3-ylacetylenyl, quinolin-3-ylacetylenyl, 4-pyridylethynyl, and the like.
xe2x80x9cHeteroaroylxe2x80x9d means an means a heteroaryl-COxe2x80x94 group wherein heteroaryl is as defined herein. Representative heteroaroyl groups include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, pyridinoyl, and the like.
xe2x80x9cHeteroaryldiazoxe2x80x9d means an heteroaryl-Nxe2x95x90Nxe2x80x94 group wherein heteroaryl is as defined herein.
xe2x80x9cHeteroarylsulphonylcarbamoylxe2x80x9d means a heteroaryl-SO2-NH-COxe2x80x94 group wherein heteroaryl is as defined herein.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a heterocyclyl-alkylene- group wherein heterocyclyl and alkylene are as defined herein. Preferred heterocyclylalkyls contain a lower alkylene moiety. A representative heteroaralkyl group is tetrahydropyranylmethyl.
xe2x80x9cHeterocyclylalkyloxyalkylxe2x80x9d means a heterocyclylalkyl-O-alkylene group wherein heterocyclylalkyl and alkylene are as defined herein. A representative heterocyclylalkyloxyalkyl group is tetrahydropyranylmethyloxymethyl.
xe2x80x9cHeterocyclyloxyxe2x80x9d means a heterocyclyl-Oxe2x80x94 group wherein heterocyclyl is as defined herein. Representative heterocyclyloxy groups include quinuclidyloxy, pentamethylenesulfideoxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, 7-oxabicyclo[2.2.1]heptanyloxy, hydroxytetrahydropyranyloxy, hydroxy-7-oxabicyclo[2.2.1]heptanyloxy, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl group as defined herein substituted with one or more hydroxy groups. Preferred hydroxyalkyls contain lower alkyl. Representative hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cN-oxidexe2x80x9d means a 
group.
xe2x80x9cOxoxe2x80x9d means a group of formula  greater than Cxe2x95x90O (i.e., a carbonyl group).
xe2x80x9cPhenoxyxe2x80x9d means a phenyl-Oxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPhenylenexe2x80x9d means a xe2x80x94phenylxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPhenylthioxe2x80x9d means a phenyl-Sxe2x80x94 group wherein the phenyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cPyridyloxyxe2x80x9d means a pyridyl-Oxe2x80x94 group wherein the pyridyl ring is optionally substituted with one or more ring system substituents as defined herein.
xe2x80x9cRing system substituentsxe2x80x9d mean substituents attached to aromatic or non-aromatic ring systems inclusive of hydrogen, alkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, nitrile, NO2, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryldiazo, heteroaryldiazo, amidino, Y1Y2Nxe2x80x94, Y1Y2N-alkylxe2x80x94, Y1Y2NCOxe2x80x94 or Y1Y2NSO2xe2x80x94, wherein Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl, or where the substituent is Y1Y2Nxe2x80x94 or Y1Y2N-alkyl- then one of Y1 and Y2 is acyl or aroyl and the other of Y1 and Y2 is hydrogen, alkyl, aryl, and aralkyl. When a ring system is saturated or partially saturated, the xe2x80x9cring system substituentxe2x80x9d further comprises methylene (H2Cxe2x95x90), oxo (Oxe2x95x90) and thioxo (Sxe2x95x90). Preferred ring system substituents are hydrogen, CF3, fluoro, alkyl, alkoxy, nitrile or NO2.
xe2x80x9cSulfamoylxe2x80x9d means a group of formula Y1Y2NSO2xe2x80x94 wherein Y1 and Y2 are defined herein. Representative sulfamoyl groups are sulfamoyl (H2NSO2xe2x80x94) and dimethylsulfamoyl (Me2NSO2xe2x80x94).
Preferred Embodiments
A process for the preparation of aldehydes and ketones according to this invention is outlined in Scheme 1 wherein Ra and Rb independently represent any aliphatic or aromatic group amenable to the solvents and reagents utilized in the processes described herein. The groups Ra and Rb may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the hydroxylamine resin. Such functional groups may be suitable protected to prevent interference with the reactions described below. For a comprehensive treatise on the protection and deprotection of common functional groups see T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Rc represents any aliphatic or aromatic group suitable for use as an organometallic reagent. 
According to the foregoing Scheme 1, a polymeric hydroxylamine resin compound 1 is coupled with a carboxylic acid derivative of formula RaCO2H to form the polymeric hydroxamic acid resin compound 2. The coupling reaction is accomplished in the presence of an activating agent as is known in the art of peptide synthesis. Representative activating agents include isopropyl chloroformate, diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1-hydroxybenzotriazole (HOBT), bis(2-oxo-3-oxazolidinyl)-phosphonic chloride (BOP-Cl), benzotriazole-1-yloxy-tris((dimethylamino)phosphonium)hexafluorophosphate (BOP), benzotriazole-1-yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBROP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazole-1-yl)-1.1.3.3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl)-1.1.3.3-tetramethyluronium hexafluoroborate (HBTU), 2-[2-oxo-1-(2H)-pyridyl]-1,1,3,3-bispentamethyleneuronoium tetrafluoroborate (TOPPipU), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), and the like. Suitable solvents for the coupling reaction include dichloromethane, DMF, DMSO, THF, and the like. Coupling times range from about 2 to about 24 hours, depending upon the resin and carboxylic acid derivative to be coupled, activating agent, solvent and temperature. The coupling is accomplished at from about xe2x88x9210xc2x0 C. to about 50xc2x0 C., preferably at about ambient temperature.
The coupling reaction is preferably accomplished at ambient temperature in DMF using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride over about 12 hours.
The polymeric hydroxaric acid resin compound 2 is then alkylated with an alkylating agent of formula RbLG, where LG is a leaving group, in the presence of a non-nucleophilic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in an inert organic solvent such as toluene to form the N-alkylated polymeric hydroxamic acid resin compound 3. The alkylating agent RbLG may be added in an equimolar amount to an excess of to about 25 molar equivalents. About 15 molar equivalents is preferred. The non-nucleophilic base may be added in an equimolar amount to an excess of to about 10 molar equivalents. About 5 molar equivalents is preferred. The leaving group LG is any group amenable to nucleophilic displacement by the nitrogen atom of the polymeric hydroxamic acid resin compound 2 under the reaction conditions described above. A preferred leaving group is halogen. A sample of the N-alkylated polymeric hydroxamic acid resin compound 3 may be subjected to acidolysis to cleave the substituted hydroxamic acid to confirm that the reaction proceeded satisfactorily.
Reaction of the polymeric N-alkylated hydroxamic acid resin compound 3 with an organometallic reagent of formula RcM, wherein Rc is an aliphatic or aromatic anion and M is a metal cation, followed by acid hydrolysis provides the ketone 4. Preferred organometallic reagents are organolithium reagents of formula RcLi and Grignard reagents of formula RcMgX wherein X is halogen. In a preferred preparation of ketones according to this aspect of the invention, the polymeric N-alkylated hydroxamic acid resin compound 3 is treated with RcMgX in diethyl ether at ambient temperature over about 18 hours, and the reaction mixture is then quenched by addition of aqueous HCl or aqueous KHSO4 to liberate the ketone 4.
Aldehydes are prepared by treatment of the polymeric N-alkylated hydroxamic acid resin compound 3 with a hydride reducing agent, followed by acid hydrolysis as shown in Scheme 1 above. Representative hydride reducing agents include LiAlH4, (iso-Bu)2AlH, LiAlH(O-t-Bu)3, LiAlH4xe2x80x94EtOH, LiAlH4xe2x80x94MeOH, and the like. Preferred reducing agents are LiAlH4 and LiAlH4xe2x80x94MeOH. The acid hydrolysis is preferably accomplished aqueous KHSO4.
As shown in Scheme 1, the N-alkylated polymeric hydroxamic acid resin compound 3 is a Weinreb-like amide useful for the synthesis of aldehydes and ketones (S. Nahm and S. Weinreb, Tet Lett. 1981, 22, 3815-3818). This N-alkylated polymeric hydroxamic acid resin compound has advantages over the previous examples of resin bound Weinreb-like amides (See Fehrentz et al., Tet. Lett., 1995, 36, 7871-7874 and Dinh et al., Tet. Lett., 1996, 37, 1161-1164) in that it can be N-alkylated with bulky lipophilic groups such as benzyl, substituted benzyl, naphthyl or any alkyl group necessary to optimize the reaction on the solid phase. The N-benzyl-O-methylpolystyrenyl moiety, for example, is well suited to form a stable metal chelated intermediate. The lipophilic benzyl group is believed to help shield the chelate adding to its stability.
A preferred process for the preparation of aldehydes and ketones is outlined in Scheme 2. In Scheme 2, xe2x80x9cPxe2x80x9d designates an amine protecting group as defined herein. 
As shown in Scheme 2 above, the polymeric hydroxylamine resin compound is protected with an amine protecting group to form the N-protected polymeric hydroxylamine resin compound 6. The N-protected polymeric hydroxylamine resin compound 6 is then alkylated as described in Scheme 1 above to form the N-alkylated N-protected polymeric hydroxylamine resin compound 7. Removal of the amine protecting group provides the mono N-alkylated polymeric hydroxylamine resin compound 8. Coupling of 8 with a carboxylic acid compound of formula RaCO2H as described above provides the polymeric N-alkylated hydroxamic acid resin compound 3, which is converted to ketone 4 or aldehyde 5 as described in Scheme 1 above.
Preferred amine protecting groups xe2x80x9cPxe2x80x9d include allyloxycarbonyl (Aloc), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (Moz), p-nitrobenzyloxycarbonyl (4-NO2-Z), trimethylsilylethoxycarbonyl (Teoc), 2,4-dimethoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, o-nitrobenzylsulfonyl (o-Nbs), p-nitrobenzylsulfonyl (p-Nbs), and 2-nitro-4-trifluoromethylbenzenesulfonyl.
The most preferred amine protecting group is allyloxycarbonyl.
In a preferred aspect of the processes described in Schemes 1 and 2 above, Ra represents the residual, non-carboxyl portion of a natural or unnatural amino acid or peptide. Accordingly, the foregoing processes present a facile route to the heretofore difficult to obtain amino acid or peptide aldehyde compounds.
In a process for preparing amino acid aldehyde or peptide amino acids according to this invention, the N-terminal nitrogen atom of the amino acid or peptide starting material is preferably protected with a suitable amine protecting group, designated herein as Pxe2x80x3. Furthermore, any functional groups contained in the amino acid or peptide side chain(s) may be suitably protected to prevent interference with the reactions described herein.
In a preferred aspect of the preparation of amino acid or peptide aldehydes described above, Rb is benzyl or substituted benzyl.
In a more preferred aspect of the preparation of amino acid or peptide aldehydes described above, Rb is benzyl or benzyl substituted with halogen, haloalkyl or alkoxy and Pxe2x80x3 is t-butyloxycarbonyl (BOC).
In addition, the N-alkylated hydroxamic acid resin compound 3 in which Ra is the residual non-carboxyl portion of a natural amino acid or peptide are amino acid or peptide aldehyde equivalents which may be stored and used to generate the corresponding amino acid or peptide aldehyde as needed by treatment with a hydride reducing agent and acid hydrolysis as described above.
Preferred polymeric N-protected hydroxylamine resin compounds include N-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
N-allyloxycarbonyl-4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)butyramide-copoly(styrene-1%-divinylbenzene)-resin,
N-allyloxycarbonyl-4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
N-allyloxycarbonyl-4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)butyramide-copoly(styrene-1% divinylbenzene) resin,
N-allyloxycarbonyl-O-hydroxylamine-2xe2x80x2-chlorotrityl-copolystyrene-1%-divinylbenzene-resin,
N-allyloxycarbonyl-O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin,
N-allyloxycarbonyl-5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valeric acid-copolystyrene-1%-divinyl benzene resin,
N-allyloxycarbonyl4-O-methylhydroxyladine-3-methoxyphenoxy-copolystyrene-1%-divinyl benzene resin,
N-allyloxycarbonyl4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
N-allyloxycarbonyl4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin and
N-allyloxycarbonyl-3-hydroxy-xanthydrolamine-copolystryene-1%-divinylbenzene resin.
The most preferred polymeric N-protected hydroxylamine resin compound is N-allyloxycarbonyl-4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin.
A process for the preparation of amines according to this invention is outlined in Scheme 3. In Scheme 3, Rd and Re independently represent H or any aliphatic or aromatic group amenable to the solvents and reagents utilized in the processes described herein, provided that Rd and Re are not both H. The groups Ra, Rb and Rc may be further substituted and may contain functional groups suitable for further chemical transformations while attached to the hydroxylamine resin. It is understood that when these functional groups possess reactivity such that they could potentially interfere with the reactions described below, such functional groups should be suitably protected. For a comprehensive treatise on the protection and deprotection of common functional groups see T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), incorporated herein by reference. Rf represents any aliphatic or aromatic group which is amenable for use as an organometallic reagent. 
According to the foregoing Scheme 3, reaction of the polymeric hydroxylamine resin compound 1 with an aldehyde or ketone 9 provides the polymeric oxime ether resin compound 10. Oxime formation is preferably accomplished at about ambient temperature by swelling the polymeric hydroxylamine resin compound 1 in a suitable inert organic solvent such as dichloromethane, followed by addition of an excess of aldehyde or ketone. Reductive cleavage of the resin, for example by reaction with NaCNBH3, or BH3THF, followed by LiAlH4 provides the amine 11. Reaction of the polymeric oxime ether resin compound 10 with an organometallic reagent of formula RfM, wherein Rf is an aliphatic or aromatic anion and M is a metal cation as defined herein, provides the polymeric (x-substituted hydroxylamine resin compound 12. Cleavage of the (xcex1-amine 13 from the resin, is accomplished, for example, using BH3THF or LiAlH4. See Y. Ukaji et al., Chem. Lett., 173, (1991) and R. P. Dieter et al., Can. J. Chem. 71, 814 (1993). Preferred metal cations are Li and MgX wherein X is halogen. With the aid of a chiral auxiliary such as a chiral benzyl hydroxyl amine linker, chiral xcex1-substituted amines will result.
A process for the preparation of lactones via radical cyclization is shown in Scheme 4. In Scheme 4, Rg, Rh and Ri are aliphatic or aryl as defined herein. 
O. As shown in the foregoing Scheme 4, the polymeric hydroxylamine resin compound 1 is reacted with the xcex1,xcex2 unsaturated carboxylic acid ester compound 14 to form the polymeric oximyl resin compound 15. Radical cyclization of 15, for example by heating in the presence of 2,2xe2x80x2-azobisisobutyronitrile (AIBN) and thiophenol in an inert organic solvent such as benzene results in formation of the polymeric g-lactone resin compound 16. Acid hydrolysis of 16, using, for example 10% aqueous HCl, provides the lactone 17. See O. Miyata et al., Tet. Lett., 37, 229-232, (1996).
A process for the preparation of carbocyclic or heterocylic compounds by radical cyclization is shown in Scheme 5. In Scheme 5, Rj, Rk and Rl are aliphatic or aryl as defined herein. The methodology described in Scheme 1 is applicable to the preparation of 5-, 6- or 7-membered rings. Carbocycles result when the phenolic oxygen atom is replaced with a carbon atom. 
According to the foregoing Scheme 5, the polymeric hydroxylamine resin compound 1 is reacted with the acetophenone compound 18 and a bromoalkene compound or o-bromobenzyl compound to form the polymeric acetophenone oxime compounds 19 or 23. Radical cyclization of 19 or 23, for example by heating in the presence of AIBN and tri-n-butyltin hydride in an inert organic solvent such as benzene results in formation of the polymeric N-cyclyl hydroxylamine resin compounds 20 or 24. Treatment of 20 or 24 with acid, preferably trifluoroacetic acid, results in formation of the cyclic hydroxamic acid compounds 21 or 25. Reductive cleavage of 20 or 24 for example using LiAlH4 as described in Scheme 3 above, results in formation of the cyclic amine compounds 22 or 26. See S. E. Booth et al., J. Chem. Soc. Commun., 1248-1249, (1991).
Hydroxamic acid compounds of formula 29, 
wherein Ar, A2, R9, R10, R11, R12 and n are defined herein, are disclosed in WO 97/24117, incorporated herein by reference. Compounds of formula 29 inhibit the production or physiological effects of tumor necrosis factor (TNF) and are useful in treating a patient suffering from a pathological condition such as inflammation or autoimmune disease characterized by a physiologically detrimental excess of TNF.
A process for the preparation of a hydroxamic acid compound of formula 29, wherein Ar, A2, R9, R10, R11, R12 and n are as defined above, according to this invention is shown in Scheme 6.
According to the foregoing Scheme 6, the carboxylic acid compound 27 is coupled to the polymeric hydroxylamine resin compound 1 as described in Scheme 1 above to form the polymeric hydroxamic acid resin compound 28. The polymeric hydroxamic acid resin compound 28 is then treated with an acid such as trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane to liberate the hydroxamic acid compound 29. A higher percentage of TFA (trifluoroacetic acid) and longer reaction times are needed to cleave the hydroxamic acid from the Wang version compared to the Rink version of the resin. During the evaporation of the TFA in the work-up to isolate the hydroxamic acid, it is found that heating the sample during concentration would generate a significant amount of the N,O-diacylated dimer of the parent hydroxamic acid as a side-product. To minimize this side reaction the reaction mixture is concentrated at or below room temperature with toluene used as an azeotrope.
A process for the preparation of a polymeric xcex1,xcex2-unsaturated alkenoate resin compound 54 according to this invention is outlined in Scheme 7. In Scheme 7, Rm is H or aliphatic, Rn is aliphatic or aromatic, and R20 and R21 are alkyl. Rm and Rn may contain additional functional groups. It is understood that these functional groups may be suitably protected to prevent interference with the reactions described below. 
According to the foregoing Scheme 7, coupling of the polymeric hydroxy resin 30 with the phosphono acetic acid compound 51 provides the polymeric phosphonoacetoxy resin compound 31. The coupling is preferably accomplished using a preformed symmetric anhydride (method i below), or using the 2,6-dichlorobenzoic acid anhydride described by Sieber, P., Tetrahedron Lett., 1987, 28, 6147-6150 (method ii below).
i) 51 (6 equiv.); diisopropylcarbodimide (3 equiv.); dichloromethane; 0xc2x0 C. 30 minutes, then 8, 4-dimethylaminopyridine (0.2 equiv.); 12 hours.
ii) 51 (3 equiv.); 2,6-dichlorobenzoyl chloride (3 equiv.); pyridine (6 equiv.); DMF; 12 hours.
The Horner-Emmons condensation of the polymeric phosphonoacetoxy resin compound 31 with the aldehyde RnCHO is then accomplished by treating 31 with an excess of a base such as potassium tert-butoxide, potassium bis(trimethylsilyl)amide or lithium bis(trimethylsilyl)amide in an organic solvent such as THF or toluene at about 0xc2x0 C. to about 25xc2x0 C. The mixture is stirred or shaken for a sufficient amount of time to quantitatively generate the resin-bound anion, generally from about 15 minutes to about 2 hours. The aldehyde RnCHO is then added and the mixture is stirred for up to three days to generate the polymeric alkenoate resin compound 32.
In an especially preferred preparation of the polymeric alkenoate resin compound 32, the polymeric phosphonoacetoxy resin compound 31 is treated with an excess of a base such as potassium tert-butoxide or lithium bis(trimethylsilyl)amide in an organic solvent such as THF at about 0xc2x0 C. to about 25xc2x0 C. The mixture is stirred or shaken for a sufficient amount of time to quantitatively generate the resin-bound anion, generally from about 15 minutes to about 2 hours. The solvent and excess base are then removed from the reaction vessel and a solution of the aldehyde in a less polar solvent mixture, comprising the solvent used in the generation of the resin-bound anion and a second, less polar solvent, is added at ambient temperature and the mixture is stirred for up to three days to generate the polymeric alkeneoate resin compound 32.
Preferred less polar solvents are alkanes such as pentane, hexane or heptane, or cycloalkanes such as cyclohexane, cyclopentane or cycloheptane. An especially preferred less polar solvent mixture is 60% cyclohexane-THF.
Use of the less polar solvent mixture in the Horner-Emmons condensation as described above presents a number of advantages over generation of the anion and condensation with the aldehyde using strong base in a polar solvent. A strong base is required to quantitatively generate the resin-bound anion. However, under the reaction conditions of strong base and a relatively polar solvent, the resin linkage was hydrolyzed resulting in a low yield of the polymeric alkeneoate resin compound 32. However, draining the solvent and excess base following essentially quantitative generation of the resin-bound anion and adding a solution of the aldehyde RnCHO in a less polar solvent mixture appears to stabilize the resin linkage toward hydrolysis and thereby results in unexpectedly high yields of the polymeric alkeneoate resin compound 32.
The polymeric alkeneoate resin compound 32 may be used for further transformations as described in Scheme 8, or the xcex1,xcex2-unsaturated acid compound 54 may be cleaved from the resin using methods commonly known in the art, for example by treating a mixture of the polymeric alkeneoate resin compound 53 in a suitable organic solvent such as dichloromethane, dichloroethane or dioxane, with acid. Cleavage is preferably accomplished at about ambient temperature using a trifluoroacetic acid (TFA)-dichloromethane solvent mixture over about 1 hour.
A process for the solid phase synthesis of the carboxylic acid compound 27, an intermediate useful for preparing the hydroxamic acid compound 29 in which Ar, A2, n and R11 are as defined herein and R9, R10 and R12 are H, is shown in Scheme 8.
The polymeric diethylphosphonoacetoxy-resin compound 31 is treated with a base such as potassium bis (trimethylsilyl) amide in an inert solvent such as toluene, at a temperature of about 0xc2x0 C., followed by an aldehyde of formula R11CHO wherein R11 is as defined above, at about ambient temperature to give the polymeric alkenoate resin compound 32.
According to the foregoing Scheme 8, reaction of the polymeric alkenoate resin compound 32a, prepared as described in Scheme 7, with a thiol of formula Ar-A2-SH, wherein Ar and A2 are as defined above, provides the polymeric alkanoate resin compound 33. The addition may be conveniently carried out under mild basic conditions, for example in the presence of lithium hydroxide at about ambient temperature.
The polymeric alkanoate resin compound 33 may then be hydrolytically cleaved by treatment with acid as described in Scheme 7, above, to prepare the carboxylic acid compound 27 wherein n is 0.
Alternatively, the polymeric alkanoate resin compound 33 may be treated with an oxidizing agent such as m-chloro-perbenzoic acid in an inert solvent such as dioxane at about ambient temperature to give the polymeric sulfoxide (n=1) or sulfone (n=2) resin compound 34. Acid hydrolysis of 34 as described in Scheme 7,above, provides the carboxylic acid compound 35.
The preparation of the polymeric hydroxylamine resin compound 1 is outlined in Scheme 9a. 
According to the foregoing Scheme 9a, a polymeric hydroxy resin compound 30 is converted to the polymeric N-hydroxylphthalimido resin compound 36 by coupling with N-hydroxyphthalimide under Mitsunobu conditions (Mitsunobu, O., Synthesis 1981, 1), by conversion of the hydroxy group to a leaving group such as the mesylate followed by nucleophilic displacement, or by reaction of the polymeric hydroxy resin compound with N-hydroxyphthalimide in the presence of an acid such as benzenesulfonic acid. Removal of the phthalimido group provides the polymeric hydroxylamine resin compound 1.
For example, when 30 is 4-(hydroxymethyl)phenoxymethyl-copoly(styrene-1%-divinylbenzene)resin (Wang resin), N-hydroxyphthalimide is coupled to the resin in the presence of diisopropylazodicarboxylate and triphenylphosphine in DMF. The phthalimido protection is removed by methylaminolysis in THF at 40xc2x0 C. The reaction is complete in about 2 hours. The use of the methylamine to cleave the phthalimide protection offers a significant advantage over the commonly used hydrazinolysis procedure (Wolf et al., Can. J. Chem., 1970, 48, 3572.
When 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin (Rink resin) is utilized, 1 is preferably prepared by reaction of the polymeric hydroxy resin compound with N-Hydroxy phthalirnide in DMF in the presence of catalytic benzene sulfonic acid to form the polymeric N-hydroxyphthalimido resin compound 36. The phthalimido protecting group is then removed by reaction with hydrazine hydrate in tert-butanol at about 60xc2x0 C. to give the corresponding polymeric hydroxylamine resin compound.
An alternative route to the polymeric N-protected hydroxylamine resin 6 is outlined in Scheme 9b. 
According to the foregoing Scheme 9, a polymeric hydroxy resin compound 30 is coupled with a N,N-diprotected hydroxylamine compound 37, wherein P and Pxe2x80x2 are amine protecting groups, as described in Scheme 8 above to form the polymeric N,N-diprotected hydroxylamine resin compound 38. The amine protecting group Pxe2x80x2 is then selectively removed to form the polymeric N-protected hydroxylamine resin compound 6.
In a preferred embodiment of the synthesis described in Scheme 9, P is benzyl and Pxe2x80x2 is allyloxycarbonyl. Selective removal of the allyloxycarbonyl protecting group is effected by treatment with tetrakis(triphenylphosphine)Palladium(0).
The N,N-diprotected hydroxylamine compound 37 is prepared by sequential introduction of the protecting groups P and Pxe2x80x2 to an O-protected hydroxylamine compound of formula H2NOP2 wherein P2 is a hydroxy protecting group. A preferred hydroxy protecting group is alkyl. The amine protecting groups P and Pxe2x80x2 are then introduced using reagents and reaction conditions well known in the art of organic synthesis. For Example, reaction of O-tert-butylhydroxylamine with allyloxychloroformate results in formation of N-allyloxycarbonyl-O-tert-butylhydroxylamine, which is then reacted with benzyl bromide to form N-benzyl-N-allyloxycarbonyl-O-tert-butylhydroxylamine. Treatment of N-benzyl-N-allyloxycarbonyl-O-tert-butylhydroxylamine with trifluoroacetic acid gives N-benzyl-N-allyloxycarbonylhydroxylamine.
The preparation of a polymeric 4-(methyl-O-methylhydroxylamine)-2-fluorophenoxymethyl resin compound is shown in Scheme 10.
According to the foregoing Scheme 10, a polymeric chloromethyl resin compound such as chloromethyl polystyrene (39, Merrifield resin) is reacted with 4-hydroxy-2-fluoroacetophenone in the presence of base to form the 4-(1-hydroxylethyl)-2-fluorophenoxymethyl resin compound 40. Reduction of the ketone group, for example using lithium borohydride in THF, provides the 4-(1-hydroxyethyl-2-fluorophenoxymethyl resin compound 41. Conversion of 41 to the hydroxyphthalimido resin compound 42, followed by removal of the phthalimido group as described in Scheme 8 above, provides the 4-(methyl-O-methylhydroxylamine)-2-fluorophenoxymethyl -copoly(styrene-1% divinylbenzene) resin compound 43.
Similarly, the preparation of a polymeric 4-(O-methylhydroxylamine)-2-fluorophenoxymethyl resin compound is shown in Scheme 10a. 
According to Scheme 10a, a polymeric chloromethyl resin of compound such as chloromethyl polystyrene (39, Merrifield resin) is reacted with Methyl-2-fluoro-4-hydroxybenzoate in the presence of base to form the 4-(methylformate)-2-fluorophenoxymethyl)-copoly(styrene-1% divinylbenzene) resin, compound 40a. Reduction of the ester group, for example with lithium aluminum hydride in THF, provided the 4-(hydroxymethyl)-2-fluorophenoxymethyl)-copoly(styrene-1% divinylbenzene) resin, compound 41a. Conversion of this to the hydroxylphthalinido resin compound 42a, followed by removal of the phthalimido group as described in Scheme 8 above, provides the 4-(O-methylhydroxylamine))-2-fluorophenoxymethyl)-copoly(styrene-1% divinylbenzene) resin, compound 43a.
The preparation of a polymeric 4-(O-methylhydroxylamine)-fluorophenoxymethyl resin compound is shown in Scheme 11.
According to the foregoing Scheme 11, a polymeric chloromethyl resin compound such as chloromethyl polystyrene (39, Merrifield resin) is reacted with 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid in the presence of base to form the 4-carboxy-2,3,5,6-tetrafluorophenoxymethyl resin compound 44. Reduction of the carboxylic acid group, for example using LiAlH4, diisobutylaluminum hydride, or BH3-THF provides the 4-hydroxymethyl-2,3,5,6-tetrafluorophenoxymethyl resin compound 45. Conversion of 45 to the hydroxyphthalimido resin compound 46, followed by removal of the phthalimido group as described in Scheme 8 above provides the 4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin compound 47.
The preparation of a polymeric 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl resin compound is shown in Scheme 12.
According to the foregoing Scheme 12, a polymeric chloromethyl resin compound is reacted with 4-phenoxy-2,3-5,6-tetrafluorophenyl 2,4-dimethoxyphenyl ketone 48 in the presence of base as described in Scheme 11 above to form the 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenylcarbonyl)-2,3,5,6-tetrafluorophenoxymethyl-resin compound 49. Reduction of the carbonyl, for example using LiBH4, provides the 4-(hydroxymethyl-2xe2x80x2,4xe2x80x2-dimethoxyphenyl)-2,3,5,6-tetrafluorophenoxymethyl resin compound 50. Conversion of 50 to the hydroxyphthalimido resin compound 51, followed by removal of the phthalimido group as described in Scheme 8 above provides the 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-0-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-resin compound 52.
Preferred polymeric hydroxylamine resin compounds have formula 1 wherein L is a linking group.
Preferred linking groups L have the formula 
wherein
A is absent or a group of formula xe2x80x94X1-Zxe2x80x94 wherein
X1 is xe2x80x94CHRxe2x80x94 or xe2x80x94CHRxe2x80x94Yxe2x80x94COxe2x80x94(CH2)nxe2x80x94 wherein R is H, alkyl, phenyl, or phenyl substituted with xe2x80x94H, alkyl, alkoxy, halogen, nitrile or xe2x80x94NO2,
Y is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94,
n is an integer from 1 to 6, and
Z is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94;
R1, R1a, R2, and R2a are independently ring system substituents; and
R3 and R4 are independently xe2x80x94H, alkyl, phenyl, or phenyl substituted with one or more substituents selected from alkyl, alkoxy, halogen nitrile and xe2x80x94NO2;
or one of R1 and R2 taken together with one of R3 and R4 and the carbon atoms to which they are attached define a linking group of formula 
wherein
R1xe2x80x2 is xe2x80x94H, alkyl, alkoxy, halogen, nitrile or xe2x80x94NO2; and
R6, R7 and R8 are independently selected from xe2x80x94H, alkyl, alkoxy, halogen, nitrile and xe2x80x94NO2.
More preferred linking groups have formula 
wherein
R1 and R2 are independently H or F;
R1a and R2a are independently ring system substituents; and
one of R3 and R4 is H and the other is H or 2,4-dimethoxyphenyl.
Representative preferred polymeric hydroxylamine resin compounds include 4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-[4-(O-methylhydroxylamine)-3-methoxyphenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1%-divinylbenzene)-resin, designated herein as 
4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-[4-(1-aminoxyethyl)-2-methoxy-5-nitrophenoxy]-(N-4-methylbenzhydryl)-butyramide-copoly(styrene-1% divinylbenzene) resin, designated herein as 
O-hydroxylamine-2xe2x80x2-chlorotrityl-copolystyrene-1%-divinylbenzene-resin, designated herein as 
O-hydroxylamine-trityl-copolystyrene-1%-divinylbenzene-resin, designated herein as 
5-(4-O-methylhydroxylamine-3,5-dimethoxyphenoxy)-valeric acid-copolystyrene-1%-divinyl benzene resin, designated herein as 
4-O-methylhydroxylamine-3-methoxyphenoxy-copolystyrene-1%-divinyl benzene resin, designated herein as 
3-hydroxy-xanthydroxylamine-copolystryene-1%-divinylbenzene resin, designated herein as 
4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(1-methyl-1-one)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(1-methyl-1-hydroxylamine)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as, 
4-(1-methyl-1-hydroxy-)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(carboxy)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(carboxyaldehyde)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(methylalcohol)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, designated herein as 
The most preferred polymeric hydroxylamine resin compounds are
4-(O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-2,3,5,6-tetrafluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(1-methyl-1-one-)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(1-methyl-1-hydroxylamine)-2-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(1-methyl-1-hydroxy-)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(carboxy)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(O-methylhydroxylamine)phenoxymethyl-copoly(styrene-1% divinylbenzene) resin,
4-(carboxyaldehyde)-3-fluorophenoxymethyl-copoly(styrene-1% divinylbenzene) resin, and 4-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl-O-methylhydroxylamine)-phenoxymethyl-copoly(styrene-1% divinylbenzene) resin.
The Rink handle (H. Rink, Tet. Lett., 28, 3787-3790, 1987) has the advantage of being cleaved under mild acidolysis for short periods of time (i.e. 10% TFA in DCM for 10-15 minutes.). However, due to the cost of the resin it is desirable to synthesize the corresponding functional resin on the Wang solid support ((a) S. S. Wang, J. Am. Chem. Soc., 1973, 95, 1328. b) Lu et al., J. Org. Chem., 1981, 46, 3433).
The polymeric hydroxylamine resin compounds in which R1a and R1b are F are especially useful as it lends itself to ready quantification of resin loading and monitoring of reactions conducted on the resin using fluorine NMR.
The methods described herein are also useful for the preparation of peptide aldehydes, ketones and hydroxamic acids. In general, this method involves coupling the carboxyl group of a suitably N-protected first amino acid to the resin to form the polymeric N-protected amino acid hydroxamic acid resin compound. The amino acid N-protecting group is then removed and the unprotected polymeric amino acid hydroxamic acid resin compound is coupled with a second suitably N-protected amino acid. This process is then repeated until the desired amino acid residues have been incorporated in the peptide.
Alternatively, peptides comprising multiple amino acids are prepared by coupling a suitably N-protected peptide subunit comprising two or more amino acids to form the polymeric N-protected peptide hydroxamic acid resin compound. The amino acid N-protecting group is then removed and the unprotected polymeric peptide hydroxamic acid resin compound is coupled with a second suitably N-protected amino acid or peptide. Thus, in addition to the sequential addition of individual amino acid subunits described above, a polypeptide may be prepared by coupling of peptide subunits.
Once the desired amino acids have been incorporated into the peptide, the polymeric peptide hydroxamic acid compound is reacted with an organometallic reagent followed by acid hydrolysis to form the peptide ketone compound; reductively cleaved to form the peptide aldehyde compound; or cleaved with acid to form the peptide hydroxamic acid compound. Any remaining protecting groups may be removed prior to or subsequently to cleavage of the peptide from the resin.
Hydroxamic acid derivatives produced in accordance with the process of this invention are useful, inter alia, as 5-LO (lipoxygenase) inhibitors. See, e.g., A. O. Stewart et al., Structure-Activity Relationships of N-Hydroxyurea 5-Lipoxygenase Inhibitors, J. Med. Chem. 1997, 40. 1955-1968.
N-protecting groups suitable for use in peptide synthesis as described herein should have the properties of being stable to the conditions of coupling to the polymeric hydroxylamine resin compound while being readily removable without destruction of the growing peptide chain or racemization of any of the chiral centers contained therein. Suitable protecting groups are 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, (a,a)dimethyl-3,5-dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2-cyano-t-butyloxycarbonyl, and the like.
Additionally, the resins of this invention are useful for constructing arrays of aldehyde, ketone or amine combinatorial libraries or arrays of aldehydes and ketones as reagents in combinatorial library synthesis, for example, reagents for the Ugi 4-component condensation (Ivar Ugi, in Isonitrile Chemistry, 1971, p. 145, Academic Press). The hydroxylamine bound resins may be used not only for single functional group transformations, but also multiple step solid phase synthesis to generate combinatorial libraries.
The functionalized resins of this invention also are useful for the parallel synthesis of a multiplicity of different aldehyde, ketone or amine end products as outlined for ketone compounds in Schemes 12a and 12b. In Schemes 12a and 12b, Rb and Rc are as defined above; n is an integer which represents the total number of different aldehyde, ketone or amine products which are to be prepared; and Ra1-Ran represent, independently, an aliphatic or aromatic group as defined herein. 
The parallel synthesis of a multiplicity of ketone compounds using a multiplicity of carboxylic acid compound Ra1CO2H-RanCO2H and a single organometallic compounds RcMgX is shown in Scheme 13a. According to Scheme 13a, the N-alkylated hydroxylamine resin compound 8, prepared as described in Scheme 2, is divided into n portions. Each portion of resin is then coupled with a different carboxylic acid compound to give n portions of polymeric N-alkylated hydroxamic acid resin compound. Each portion of polymeric N-alkylated hydroxamic acid resin compound is then reacted with a Grignard reagent of formula RcX and subjected to acid hydrolysis to give n portions of ketone derived from a single organometallic reagent. 
The parallel synthesis of n different ketone compounds derived from a single carboxylic acid compound RaCO2H and n different organometallic compounds Rc1MgBr to RcnMgBr is outlined in Scheme 13b above. According to Scheme 13b, the polymeric N-alkylated hydroxylamine resin compound is coupled with a carboxylic acid of formula RaCO2H. The resulting polymeric N-alkylated hydroxamic acid resin compound is then divided into n portions, and each portion of polymeric N-alkylated hydroxamic acid resin compound is then reacted with a different Grignard reagent Rc1-RcnMgBr and subjected to acid hydrolysis to give n different ketone compounds derived from a single carboxylic acid compound.
The functionalized resins of this invention are also useful for constructing a combinatorial library of ketones or amines as illustrated for the ketone library derived from 4 carboxylic acid compounds and 4 Grignard reagents as outlined in Scheme 14.
According to the foregoing Scheme 14, the polymeric N-alkylated hydroxylamine resin compound 8 is divided in 4-portions, and each portion is coupled with a different carboxylic acid compound to prepare 4 different polymeric N-alkylated hydroxamic acid resin compounds. The 4 portions of polymeric N-alkylated hydroxamic acid resin compounds are then mixed together to form a single portion which is then divided into 4 portions of polymeric N-alkylated hydroxamic acid resin compounds, in which each portion contains approximately equal amounts of each individual polymeric N-alkylated hydroxamic acid resin compound. Each of the 4 portions is then reacted with a different Grignard reagent Rc1-Rc4MgBr and subjected to acid hydrolysis to give 4 portions of ketone compound, each of which contains 4 compounds representing the products of reaction of each of the 4 different polymeric N-alkylated hydroxamic acid resin compounds with a single Grignard reagent. In this manner a combinatorial library containing a multiplicity of ketone compounds may be quickly constructed.
In a similar manner, a combinatorial library of peptides may be assembled by repeating the dividing-recombining sequence for each amino acid or peptide building block.
The foregoing may be better understood by reference to the following Examples, which are presented for illustration and not intended to limit the scope of the invention.